Secondary binding site of dipeptidyl peptidase IV (DPIV)

Abstract

The present application relates to the secondary binding site of dipeptidyl peptidase IV, its relationship amongst substrates and to the modulation of substrate specificity of dipeptidyl peptidase IV (DP IV, synonym: DPP IV, CD26, EC 3.4.14.5). The application relates further to compounds that bind to the secondary binding site of DP IV and their use to modulate the substrate specificity of DP IV; methods of treatment of various DP IV mediated disorders; and screening methods for the identification of secondary binding sites on DP IV and DP IV-like enzymes.

1 - 25 . (canceled)  
     
     
         26 . A method for the treatment of metabolic diseases in a mammal comprising co-administration to said mammal of (i) a compound capable of binding to a secondary binding site of DPIV and DPIV like enzymes and (ii) at least one anti-diabetic agent.  
     
     
         27 . A method for the treatment of metabolic diseases in a mammal comprising co-administration to said mammal of (i) a compound capable of binding to a secondary binding site of DPIV and DPIV like enzymes and (ii) at least one anti-diabetic agent selected from the group consisting of: 
 DP IV inhibitors;    PPAR agonists;    biguanides, e.g. metformin, phenformin or buformin;    protein tyrosin phosphatase-1B (PTP-1B) inhibitors;    insulin and insulin mimetics;    sulfonylureas and other insulin secretagogues;    α-glucosidase inhibitors or acarbose;    glucagon receptor agonists;    GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;    GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists or teduglutide;    exendin-4, exendin-4 mimetics, exenatide;    GIP, GIP mimetics, and GIP receptor agonists;    PACAP, PACAP mimetics, and PACAP receptor 3 agonists;    PYY, PYY mimetics, PYY receptor agonists, and PYY receptor antagonists;    one or more cholesterol lowering agents selected from the group consisting of: 
 HMG-CoA reductase inhibitors,  
 sequestrants,  
 nicotinyl alkohol, nicotinic acid and salts thereof,  
 PPARα agonists,  
 PPARγ agonists,  
 PPARα/γ dual agonists,  
 inhibitors of cholesterol absorption,  
 acyl CoA:cholesterol acyltransferase inhibitors, and  
 antioxidants;  
   PPARδ agonists;    anti-obesity compounds;    an ileal bile acid transporter inhibitor; and    anti-inflammatory agents.    
     
     
         28 . The treatment method according to  claim 27  wherein the compound is selected from the group comprising: a consensus sequence of the GRF-peptide family, TFTSDY (SEQ ID NO: 1), TFTDDY (SEQ ID NO:4), H-Ser-D-Glu-Thr-Gly-D-Val-D-Lys-D-Val-OH, and compounds of formulas a) to d):  
       
         
           
           
               
               
           
         
       
     
     
         29 . The treatment method according to  claim 27  wherein the anti-diabetic agent is selected from DPIV inhibitors, metformin, exenatide, exendin-4, acarbose, insulin, and sulfonylureas.  
     
     
         30 . The treatment method according to  claim 27  wherein the metabolic disease is selected from Syndrome X, impaired glucose tolerance, glucosuria, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, metabolic acidosis, hyperglycemia, diabetes mellitus, diabetic neuropathy and nephropathy and of sequelae caused by diabetes mellitus in mammals, metabolism-related hypertension and cardiovascular sequelae caused by hypertension in mammals.  
     
     
         31 . The treatment method according to  claim 27  for the prophylaxis and/or treatment of skin diseases, diseases of the mucosa, autoimmune diseases, inflammatory conditions, psychosomatic, neuropsychiatric and depressive illnesses, such as anxiety, depression, sleep disorders, chronic fatigue, schizophrenia, epilepsy, nutritional disorders, spasm and chronic pain, atherosclerosis and its sequelae, vascular restenosis, irritable bowel syndrome, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, other inflammatory conditions, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, ovarian hyperandrogenism (polycystic ovarian syndrome), growth hormone deficiency, neutropenia, tumor metastasis, benign prostatic hypertrophy, gingivitis, osteoporosis, and other conditions.  
     
     
         32 . A pharmaceutical composition comprising a compound capable of binding to a secondary binding site of DP IV and DP IV like enzymes, at least one anti-diabetic agent and a pharmaceutically acceptable carrier therefore.  
     
     
         33 . The pharmaceutical composition of  claim 32  wherein said at least one anti-diabetic agent is selected from the group consisting of: 
 DP IV inhibitors;    PPAR agonists;    biguanides, e.g. metformin, phenformin or buformin;    protein tyrosin phosphatase-1B (PTP-1B) inhibitors;    insulin and insulin mimetics;    sulfonylureas and other insulin secretagogues;    α-glucosidase inhibitors or acarbose;    glucagon receptor agonists;    GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;    GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists or teduglutide;    exendin-4, exendin-4 mimetics, exenatide;    GIP, GIP mimetics, and GIP receptor agonists;    PACAP, PACAP mimetics, and PACAP receptor 3 agonists;    PYY, PYY mimetics, PYY receptor agonists, and PYY receptor antagonists;    one or more cholesterol lowering agents selected from the group consisting of: 
 HMG-CoA reductase inhibitors,  
 sequestrants,  
 nicotinyl alkohol, nicotinic acid and salts thereof,  
 PPARα agonists,  
 PPARγ agonists,  
 PPARα/γ dual agonists,  
 inhibitors of cholesterol absorption,  
 acyl CoA:cholesterol acyltransferase inhibitors, and  
 antioxidants;  
   PPARδ agonists;    anti-obesity compounds;    an ileal bile acid transporter inhibitor; and    anti-inflammatory agents.    
     
     
         34 . The pharmaceutical composition of  claim 32  wherein the compound is selected from the group comprising: a consensus sequence of the GRF-peptide family, TFTSDY (SEQ ID NO: 1), TFTDDY (SEQ ID NO:4), H-Ser-D-Glu-Thr-Gly-D-Val-D-Lys-D-Val-OH, and compounds of formulas a) to d):  
       
         
           
           
               
               
           
         
       
     
     
         35 . The pharmaceutical composition of  claim 32  wherein said compound is TFTSDY (SEQ ID NO:)1 or TFTDDY (SEQ ID NO:4).  
     
     
         36 . The pharmaceutical composition of  claim 32  wherein said compound is H-Ser-D-Glu-Thr-Gly-D-Val-D-Lys-D-Val-OH.  
     
     
         37 . The pharmaceutical composition of  claim 32  wherein said compound capable of binding to a secondary binding site of DP IV and/or DP IV-like enzymes modulates the selectivity and/or activity of DP IV or DP IV-like enzymes in a mammal.  
     
     
         38 . The pharmaceutical composition of  claim 32  wherein said compound capable of binding to a secondary binding site of DP IV and/or DP IV-like enzymes substantially prevents of the interaction of DPIV or DPIV-like enzymes with their binding proteins in a mammal.  
     
     
         39 . The pharmaceutical composition of  claim 32  wherein said secondary binding site of DPIV and DPIV like enzymes comprises the amino acid residues L90, E91, T152, W154, W157, R310, Y330, R318, Y416, S460, K463, E464 and R560 of DP IV.  
     
     
         40 . The pharmaceutical composition of  claim 32  wherein said secondary binding site of DPIV and DPIV like enzymes comprises the amino acid residues Glu361 and Ile407 and Nε2 of His363 of DP IV.  
     
     
         41 . The treatment method according to  claim 27  wherein the compound blocks the product release site of DP IV and/or DP IV-like enzymes.  
     
     
         42 . The treatment method according to  claim 27  wherein the compound substantially prevents the tetramerization of DP IV and/or DP IV-like enzymes.  
     
     
         43 . The treatment method according to  claim 27  wherein the compound comprises 3 to 20 amino acid residues.  
     
     
         44 . The treatment method according to  claim 27  wherein the compound comprises 5 to 12 amino acid residues.  
     
     
         45 . The treatment method according to  claim 27  wherein the compound comprises 5 to 7 amino acid residues.